Highlights from Recent Cancer Literature
Journal: Cancer Research (2014)

Tang Y, Gholamin S, Schubert S, Willardson MI, Lee A, Bandopadhayay P, et al. Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat Med 2014;20:732–40.The Hedgehog (HH) inhibitor vismodegib, which blocks the G-protein coupled protein Smoothened (SMO), is used in advanced basal cell carcinoma. Noncanonical activation of GLI proteins downstream of Smoothened promotes resistance. To identify HH inhibitors that act downstream of Smoothened, Tang and colleagues tested JQ1, an inhibitor of BET-bromodomain proteins. JQ1 inhibited HH-dependent readouts during zebrafish embryogenesis and in mouse fibroblasts. Consistent with the specificity of JQ1 action, knockdown of BET bromodomain proteins attenuated HH-dependent readouts, also blocking the increased BRD4 occupancy on the GLI promoters observed in response to HH. JQ1 attenuated viability and expression of HH target genes in diverse HH-dependent cancer cells both in vitro and in vivo, including cells resistant to Smoothened inhibitors. Thus, BET proteins are critical regulators of GLI transcription, and BET inhibitors represent a potential treatment for HH-dependent cancers resistant to Smoothened inhibitors.Knelson EH, Gaviglio AL, Nee JC, Starr MD, Nixon AB, Marcus SG, Blobe GC. Stromal heparan sulfate differentiates neuroblasts to suppress neuroblastoma growth. J Clin Invest 2014;124:3016–31.Heparan sulfate proteoglycans (HSPG) regulate cell–cell and cell–extracellular matrix signaling. HSPGs, including TGFBR3, GPC3, and SDC4, exhibit increased expression in early-stage and stromal-rich tumors, including neuroblastoma. Application of soluble HSPGs or coculture with Schwannian stromal cells expressing HSPGs was demonstrated by Knelson and colleagues to promote differentiation of neuroblastoma cell lines. HSPGs are comprised of a protein core and glycosaminoglycan (GAG) side chains. Mutating one of the GAG attachment sites partially blocked differentiation. These data are consistent with the association of multiple HSPGs, containing different core proteins, with the differentiation phenotype. Differentiation of neuroblastoma cells was promoted by the HS/heparin mimetic 2-O, 3-O-desulfated heparin, and in vivo tumor growth was suppressed. Thus, extracellular HSPGs, including those derived from the stroma, can promote cellular differentiation and could be exploited as a therapeutic option in neuroblastoma.Mashima T, Soma-Nagae T, Migita T, Kinoshita R, Iwamoto A, Yuasa T, et al. TRIB1 supports prostate tumorigenesis and tumor-propagating cell survival by regulation of endoplasmic reticulum chaperone expression. Cancer Res; Published OnlineFirst June 24, 2014; doi:10.1158/0008-5472.CAN-13-3718.Mashima and colleagues screened molecules that regulate growth in three-dimensional (3D) spheroid cell culture. This analysis identified TRIB1, a member of the Trib family of serine/threonine kinase-like proteins, as essential for prostate cancer growth and survival. TRIB1 was overexpressed in prostate cancer patient specimens. Silencing of TRIB1 inhibited growth of prostate cancer cells in 3D culture (and in xenografts) and was reversed by reintroduction of TRIB1. Additionally, TRIB1 was shown to play a role in endoplasmic reticulum (ER) pathways and was required for expression of the ER chaperone, GRP78 (HSPA5). GRP78 itself plays a critical role in prostate tumorigenesis. Interestingly, GRP78 was preferentially expressed in a subpopulation of tumor propagating prostate cancer cells, which were sensitive to TRIB1 and GRP78 depletion. Thus, the TRIB1-GRP78 axis drives prostate tumorigenesis and tumor propagating cells, suggesting TRIB1 as a therapeutic target.Chaudhuri O, Koshy ST, Branco da Cunha C, Shin JW, Verbeke CS, Allison KH, et al. Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium. Nat Mater 2014 Jun 15 [Epub ahead of print].Chaudhuri and colleagues generated distinct 3D microenvironments in a model system whereby stiffness and availability of extracellular matrix ligands were controlled independently. Increasing stiffness alone was sufficient to transform polarized and growth-arrested nonmalignant MCF10A mammary epithelial cells. Importantly, stiffness-transformed cells exhibit elevated PI3K activity, a lack of basement-membrane deposition, and collective invasion resembling well-differentiated estrogen receptor-α–positive invasive ductal carcinomas. Surprisingly, this stiffness-induced malignant phenotype was fully abrogated by increasing the concentration of basement membrane, and not RGD ligands in the stiff 3D microenvironments. This effect was attributed to elevated α6β4-integrin signaling in hemidesmosomes following ligand binding, suggesting that the microenvironment-induced transformation is dependent on integrin engagement. These findings suggest β4-integrin as a mediator of mechanotransduction and indicate that analysis of the balance between tissue stiffness and matrix composition may provide prognostic value for breast cancer progression.Li X, Xu Z, Du W, Zhang Z, Wei Y, Wang H, et al. Aiolos promotes anchorage independence by silencing p66Shc transcription in cancer cells. Cancer Cell 2014;25:575–89.Li and colleagues demonstrate that lung cancer cells co-opt and exploit a hematopoietic-specific transcription factor, Aiolos (IKZF3), to evade anoikis (cell death triggered by loss of anchorage) and promote survival. High levels of Aiolos correlate with poor survival in lung cancer patients. Aiolos-positive cancer cells showed increased anchorage independence in vitro and augmented metastasis in vivo following tail vein injection. Aiolos expression was associated with downregulation of adhesion-related genes, resulting in attenuated cell-matrix sustained loss of adhesion receptors, including p66Shc (SHC1). Aiolos reconfigured chromatin structure within the SHC1 gene, silencing the anoikis-regulating p66Shc isoform, but not the survival-promoting p52Shc variant. This study shows that carcinoma cells gain metastatic potential through acquiring a hematopoietic lineage-specific transcription factor that confers anchorage independence.Godinho SA, Picone R, Burute M, Dagher R, Su Y, Leung CT, et al. Oncogene-like induction of cellular invasion from centrosome amplification. Nature 2014;510:167–71.Centrosome amplification in cancer is associated with advanced-stage disease, recurrence, and poor survival. Godinho and colleagues hypothesized that centrosome amplification provides a selective advantage to cancer cells. Centrosome amplification, genetically and chemically induced in MCF10A cells and in keratinocytes, drove a proinvasive phenotype. Centrosome-amplified cells acquired a scattered phenotype suggesting a loss in cell–cell junctions. Invasion induced by centrosome amplification was dependent on decreased cell–cell adhesion and activation of RAC1. Inhibition of the ARP2/3 complex, downstream of RAC1, partially rescued the centrosome-induced defects in cell–cell adhesion. Furthermore, microtubule nucleation was necessary for invasion, demonstrated by knockdown of CEP192. Thus, centrosome amplification may promote tumor cell invasion and augment oncogenic-induced invasive properties.Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.